Application of ARE-reporter systems in drug discovery and safety assessment.

The human body is continuously exposed to xenobiotics and internal or external oxidants. The health risk assessment of exogenous chemicals remains a complex and challenging issue. Alternative toxicological test methods have become an essential strategy for health risk assessment. As a core regulator of constitutive and inducible expression of antioxidant response element (ARE)-dependent genes, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in maintaining cellular redox homeostasis. Consistent with the properties of Nrf2-mediated antioxidant response, Nrf2-ARE activity is a direct indicator of oxidative stress and thus has been used to identify and characterize oxidative stressors and redox modulators. To screen and distinguish chemicals or environmental insults that affect the cellular antioxidant activity and/or induce oxidative stress, various in vitro cell models expressing distinct ARE reporters with high-throughput and high-content properties have been developed. These ARE-reporter systems are currently widely applied in drug discovery and safety assessment. In the present review, we provide an overview of the basic structures and applications of various ARE-reporter systems employed for discovering Nrf2-ARE modulators and characterizing oxidative stressors.

Physiologically-based toxicokinetic modeling of human dermal exposure to diethyl phthalate: Application to health risk assessment.

Diethyl phthalate (DEP) has been most frequently detected in personal care products (PCPs) as a solvent followed by indoor air as one of the semi-volatile organic compounds (SVOCs). Human exposure to DEP predominantly occurs via dermal uptake. However, the available physiologically based toxicokinetics (PBTK) models are developed in rats for risk assessment of DEP exposure resulting from the oral than dermal pathway. To address this issue, DEP in simulated PCPs was dermally administrated to five adult volunteers at real population levels. Following the construction of a dermal absorption model for DEP, the dermal PBTK modeling of DEP involving PCPs and air-to-skin exposure routes in humans was developed for the first time. The data of monoethyl phthalate (MEP) in serum or urine obtained from published human studies and this study were applied to calibrate and validate the developed dermal PBTK model. Monte Carlo simulation was used to evaluate model uncertainty. The dermal absorption fraction of DEP was obtained to be 56.2% for PCPs exposure and 100% for air-to-skin exposure, respectively. Approximate 24.9% of DEP in exposed skin became absorbed into systemic circulation. Model predictions were generally within 2-fold of the observed MEP levels in human serum or urine. Uncertainty analysis showed 90% of the predicted variability (P95/P5) fell within less than one order of magnitude. Assuming human intake of 5 mg/kg bw per day, the predicted serum area under the curve at steady state of DEP from the dermal route was 1.7 (PCPs) and 2.4 (air) times of those from the peroral route, respectively. It suggested that dermal exposure to DEP would pose greater risk to human health compared with oral exposure. The application of the developed dermal PBTK model provides a valuable insight into health risk assessment of DEP in humans.

Spatial-temporal distribution, cancer risk, and disease burden attributed to the dietary dioxins exposure of Chinese residents.

This study analyzed the characteristics of dioxins represented by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as dioxin-like polychlorinated biphenyls (dl-PCBs) in food from China. The spatial-temporal distribution characteristics of dioxins dietary intake, cancer risk, and disease burden were evaluated among the Chinese population. In the temporal dimension, descending trends in animal-origin-food were found both in dietary intake PCDD/Fs and dl-PCBs, with the reverse for plant-origin-food. The probability assessments of dietary intakes showed that after 2007, the exposure level of PCDD/Fs through diets of urban and rural residents in China was significantly lower than that before 2007 (p < 0.05). The spatial distribution results showed that the southern coastal regions were high exposure regions of dietary intakes of PCDD/Fs and dl-PCBs. Cancer risk and disease burden of dietary dioxins showed downward trends after 2007 both under an average exposure scenario and an extreme exposure scenario. After 2007, the disease burden resulting from exposure to dl-PCBs became higher and approached the median of values reported by the WHO, while the disease burden resulting from exposure to PCDD/Fs approached the lower level of 95% CI reported by the WHO. The results indicate that accompanying the National Implementation Plan and a series of subsequent scientific guidance documents launched for reducing dioxins pollution in 2007, the health benefits and the health risks caused by dl-PCBs should be given further attention and evaluation in future studies.

Cadmium exposure reprograms energy metabolism of hematopoietic stem cells to promote myelopoiesis at the expense of lymphopoiesis in mice.

Cadmium (Cd) is a highly toxic heavy metal in our living environment. Hematopoietic stem cells (HSC) are ancestors for all blood cells. Therefore understanding the impact of Cd on HSC is significant for public health. The aim of this study was to investigate the impact of Cd2+ on energy metabolism of HSC and its involvement in hematopoiesis. Wild-type C57BL/6 mice were treated with 10 ppm of Cd2+ via drinking water for 3 months, and thereafter glycolysis and mitochondrial (MT) oxidative phosphorylation (OXPHOS) of HSC in the bone marrow (BM) and their impact on hematopoiesis were evaluated. After Cd2+ treatment, HSC had reduced lactate dehydrogenase (LDH) activity and lactate production while having increased pyruvate dehydrogenase (PDH) activity, MT membrane potential, ATP production, oxygen (O2) consumption and reactive oxygen species (ROS), indicating that Cd2+ switched the pattern of energy metabolism from glycolysis to OXPHOS in HSC. Moreover, Cd2+ switch of HSC energy metabolism was critically dependent on Wnt5a/Cdc42/calcium (Ca2+) signaling triggered by a direct action of Cd2+ on HSC. To test the biological significance of Cd2+ impact on HSC energy metabolism, HSC were intervened for Ca2+, OXPHOS, or ROS in vitro, and thereafter the HSC were transplanted into lethally irradiated recipients to reconstitute the immune system; the transplantation assay indicated that Ca2+-dependent MT OXPHOS dominated the skewed myelopoiesis of HSC by Cd2+ exposure. Collectively, we revealed that Cd2+ exposure activated Wnt5a/Cdc42/Ca2+ signaling to reprogram the energy metabolism of HSC to drive myelopoiesis at the expense of lymphopoiesis.

Blood lead levels of Chinese children from 1991 to 2020: Based on Monte Carlo simulation.

Chinese children have been exposed to high level of lead due to polluted air, dust, contaminated foods and water, etc. In this research, we investigated published blood lead levels (BLLs) reflecting 1,057,832 Chinese children aged at 0-12 and teenagers aged at 13-18 in the past 30 years (1991-2020). The data mining and estimation were performed innovatively by Monte Carlo simulation to remedy the skewed distribution-induced bias. The temporal trend of Chinese children's BLLs showed an obvious decrease in the past decades from 88.74 µg/L (Geometric SD = 4.09) during 1991-1995 to 27.32 µg/L (Geometric SD = 4.18) during 2016-2020. This study also indicated that children's BLLs of Yunnan, Guizhou, Shanxi were at relatively high levels and most provinces showed a downward trend. Chinese boys aged at 1-18 years old had higher BLLs (GM: 44.03 µg/L) compared to girls (GM: 41.32 µg/L) (p < 0.001). At different age groups, Chinese children's BLLs were 42.04 µg/L (1-3 years old), 52.88 µg/L (4-6 years old), 50.49 µg/L (7 and above years old), respectively. Although the BLLs of Chinese children exhibited a continuous declined trend in the past 30 years, it was still higher than that in developed countries, which indicated that more efforts are needed in children's BLLs control.

Temporal growth and spatial distribution of the fast food industry and its relationship with economic development in China - 2005-2012.

The fast food (FF) industry has expanded rapidly in China during the past two decades, in parallel with an increase in the prevalence of obesity. Using government-reported longitudinal data from 21 provinces and cities in China, this study examined the growth over time and the spatial distribution patterns of the FF industry as well as the key social economic factors involved. We visualized the temporal and geographic distributions of FF industry development and conducted cross-sectional and longitudinal spatial analysis to assess associations between macroeconomic conditions, population dynamics, and the growth and distributional changes of the industry. It grew faster in the southeast coastal (more economically developed) areas since 2005 than in other regions. The industry was: 1) highly correlated with Gross Domestic Product; 2) highly correlated with per capita disposable income for urban residents; 3) moderately correlated with urban population; and 4) not correlated with an increase of population size. The mean center of the FF industry shifted westward as the mean center of the GDP moved in the same direction, while the mean center of the population shifted eastward. The results suggest that the rapid FF industry expansion in China was closely associated with economic growth and that improving the food environment should be a major component in local economic development planning.

A Review of the Growth of the Fast Food Industry in China and Its Potential Impact on Obesity.

The fast-food (FF) industry and obesity rates have rapidly increased in China. This study examined the FF industry growth in China, key factors contributing to the growth, and the association between FF consumption (FFC) and obesity. We collected related data from multiple sources and conducted analysis including linear regression analysis on the increase in FF revenue. It was found that FF industry in China is large, with over two million FF facilities. Its total revenue (in million US$) increased from 10,464 in 1999 to 94,218 in 2013, and by 13% annually since 2008. Increased income, urbanization, busier lifestyle, speedy FF service, assurance of food safety, new brands and foods have stimulated demand for FF. Studies have linked FFC with obesity risk, including a few reporting a positive association between FFC and obesity in China. Rapid expansion of Western-style FF restaurants has also stimulated local FF industry growth. Government regulation and public health education need to address the health consequences of rapidly increasing FFC. Lessons learned in China will help other countries.

Occurrence of regulated and emerging iodinated DBPs in the Shanghai drinking water.

Drinking water chlorination plays a pivotal role in preventing pathogen contamination against water-borne disease. However, chemical disinfection leads to the formation of halogenated disinfection by products (DBPs). Many DBPs are highly toxic and are of health concern. In this study, we conducted a comprehensive measurements of DBPs, including iodoacetic acid (IAA), iodoform (IF), nine haloacetic acids and four trihalomethanes in drinking waters from 13 water plants in Shanghai, China. The results suggested that IAA and IF were found in all the water treatment plants, with maximum levels of 1.66 µg/L and 1.25 µg/L for IAA and IF, respectively. Owing to deterioration of water quality, the Huangpu River has higher IAA and IF than the Yangtze River. Our results also demonstrated that low pH, high natural organic matter, ammonia nitrogen, and iodide in source waters increased IAA and IF formation. Compared to chlorine, chloramines resulted in higher concentration of iodinated DBP, but reduced the levels of trihalomethanes. This is the first study to reveal the widespread occurrence of IAA and IF in drinking water in China. The data provide a better understanding on the formation of iodinated disinfection byproducts and the findings should be useful for treatment process improvement and disinfection byproducts controls.

Change of water consumption and its potential influential factors in Shanghai: a cross-sectional study.

BACKGROUND: Different water choices affect access to drinking water with different quality. Previous studies suggested social-economic status may affect the choice of domestic drinking water. The aim of this study is to investigate whether recent social economic changes in China affect residents' drinking water choices. METHODS: We conducted a cross-sectional survey to investigate residents' water consumption behaviour in 2011. Gender, age, education, personal income, housing condition, risk perception and personal preference of a certain type of water were selected as potential influential factors. Univariate and backward stepwise logistic regression analyses were performed to analyse the relation between these factors and different drinking water choices. Basic information was compared with that of a historical survey in the same place in 2001. Self-reported drinking-water-related diarrhoea was found correlated with different water choices and water hygiene treatment using chi-square test. RESULTS: The percentage of tap water consumption remained relatively stable and a preferred choice, with 58.99% in 2001 and 58.25% in 2011. The percentage of bottled/barrelled water consumption was 36.86% in 2001 and decreased to 25.75% in 2011. That of household filtrated water was 4.15% in 2001 and increased to 16.00% in 2011. Logistic regression model showed strong correlation between one's health belief and drinking water choices (P < 0.001). Age, personal income, education, housing condition, risk perception also played important roles (P < 0.05) in the models. Drinking-water-related diarrhoea was found in all types of water and improper water hygiene behaviours still existed among residents. CONCLUSIONS: Personal health belief, housing condition, age, personal income, education, taste and if worm ever founded in tap water affected domestic drinking water choices in Shanghai.